Project 1: The studies reported in this interval and previously establish the unexpected finding that the development of fibrosis in a chronic inflammation of the gastrointestinal tract is an outgrowth of the inflammation itself, namely the production of Th17 cytokines and the induction of IL-13 synthesis. In addition, they show that fibrosis was ultimately dependent on IL-13 signaling via IL-13Ralpha2 that results in the production of TGF-beta1. The particular focus of the study reported here is the downstream events of the fibrotic program set in motion by the production of TGF-beta1. Evidence is presented that the latter cytokine results in the production of IGF-1 and Egr-1, two factors that mediate old myofibroblast apoptosis and new myofibroblast collagen formation. [unreadable] [unreadable] Project 2: As pointed out above, "conventional wisdom" holds that breaches of the epithelial barrier by commensal organisms in the mucosal lumen leads to colitis. In fact, it is widely believed that defects in epithelal barrier function is a cause of Crohn's disease. These studies will require a modification in this view. They provide strong evidence that minor and/or transient breaches of barrier function have, in fact, the opposite effect: the induction of regulatory T cells that prevent colitis. This, in a sense, is not unexpected when it is pointed out that cross-talk between the commensal flora and immune elements in the lamina propria is known to occur even in the absence of disruptions in barrier function. These findings will have important impact on the interpretation of the significance of changes in epithelial barrier function in inflammatory bowel disease.